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Categorization of cytokines into pro-atherogenic and anti-atherogenic cytokines based on their effects in mouse atherosclerosis models. (A) The balance between pro-inflammatory and anti-inflammatory cytokines is crucial for lesion development and imbalance is colloquially referred to exacerbate atherosclerotic disease. (B) Overview of the cytokines with consistent anti-atherogenic effects (green circle), pro-atherogenic effects (red circle), or variable, dual function (intersection).
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In the past few years, inflammation has emerged as a major driving force of atherosclerotic lesion development. It is now well-established that from early lesion to vulnerable plaque formation, numerous cellular and molecular inflammatory components participate in the disease process. The most prominent cells that invade in evolving lesions are mon...
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Context 1
... interleukins, macrophage- associated cytokines such as tumour necrosis factor (TNF)-a, macrophage migration inhibitory factor (MIF), interferon (IFN)-g and colony stimulating factors (CSFs) have emerged as key factors in the pathogenesis of atherosclerosis. 2,6 More refined analysis of local vascular inflammation and the cytokines expressed in atherosclerotic plaques revealed that there is a balance between pro-inflammatory and anti- inflammatory cytokines and that this balance is crucial for lesion development ( Figure 2A). For example, the secreted cytokines of type 1 CD4þ T-helper cells (T H 1 cells) such as interleukin-2 (IL-2), IL-12, IFN-g, TNF-a and TNF-b are pro-inflammatory and exacerbate atherosclerotic disease, whereas T H 2 cytokines such as IL-4, IL-5, IL-10, and IL-13 are considered to be mainly atheroprotective and can counteract T H 1 cytokine activity/production. [7][8][9] Notably, this attractive black-and-white concept of T H 1 and T H 2 responses controlling the development of atherosclerosis may not be true at all stages of plaque development. ...Context 2
... 2 provides a global overview on the overall effects of these cytokines on plasma cholesterol and atherosclerosis in C57/BL6, ApoE 2/2 , and LDLr 2/2 mice. An important outcome of this survey is that several cyto- kines show explicit and consistent pro-atherogenic effects, generally independent of the experimental approach and conditions chosen: IL-1, IL-12, IL-18, TNF-a, MIF, IFN-g, and M-CSF all display pro-atherogenic characteristics while IL-10 clearly has anti-atherogenic properties ( Figure 2B). Some cytokines have a dual character and show variable effects: IL-4, IL-6, and GM-CSF can have pro-or anti- atherogenic properties, depending on the mouse model and gender used, disease stage analysed, and dietary con- ditions applied. ...Similar publications
The study of human endometrial-embryonic interactions is complicated by the disruptive impact of endometrial sample collection on the process of implantation itself. Endometrial secretion analysis is a novel technique, non-disruptive to implantation. The primary aim of this prospective cohort study was to explore whether a cytokine profile predicti...
Citations
... The previous study found that many cytokines, including IL-1, IL-12, and IL-18, were consistently proatherogenic and were thought to be the primary causes of atherosclerosis. (25) SG significantly reduces adipose tissue mass and has been shown to decrease TNF-α by upregulating adiponectin. It was confirmed in this study that there was a decrease of TNF-α in the obese and DM rats who underwent SG compared to the obese and DM rats group. ...
BACKGROUND: Sleeve gastrectomy (SG) is one option to significantly reduce body weight while also protect the cardiovascular system by controlling hyperglycemia and inflammatory markers. Secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-1 could induce obesity- and diabetes mellitus (DM)-related inflammation, however its association with SG procedure has not been elucidated well. Therefore, TNF-α and IL-1 gene expression on the abdominal aorta of obese and DM rats that went through SG procedure were evaluated.METHODS: Fifteen rats were divided into 3 groups: lean-non-DM rats model (C1 group), obese-DM rats model (C2 group), and obese-DM rats model underwent SG (T group). Before and 10 days after the SG procedure, rats’ body weight and fasting blood glucose (FBG) were measured. Ten days after the procedure, TNF-α and IL-1 gene expression were also evaluated by PCR.RESULTS: In the end of study, mean body weight and FBG levels in C1 group (231.80±4.32 gram; 68.60±2.07 mg/dL) and T group (232.00±5.33 gram; 114.40±3.20 mg/dL) were significantly lower than in C2 group (264.60± 3.28 gram; 271.00±6.89 mg/dL). TNF-α and IL-1 gene expressions were also found to be significantly lower in the C1 group (1.01±0.01 rfu; 1.01±0.01 rfu) and T group (1.97±0.57 rfu; 1.21±0.78 rfu) compared to the C2 group (224.12±47.59 rfu; 1.85±0.73 rfu).CONCLUSION: SG could decrease body weight and FBG, as well as TNF-α and IL-1 gene expression in the abdominal aorta of rats with obesity and DM, hence SG could be a useful method in reducing body weight and controlling hyperglycemia and inflammatory markers.KEYWORDS: sleeve gastrectomy, TNF-α, interleukin-1, obesity, diabetes mellitus
... The second is antiatherogenic such as IL-10. The third is cytokines that can exert pro-or antiatherogenic effects depending on the experimental conditions, such as IL-4, IL-6, and macrophage-associated cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) (Kleemann et al., 2008). In this regard, some studies that use antiinflammatory therapy targeting the immune system by modulating or blocking interleukins, also known as anticytokine therapy, such as canakinumab, a highly specific human anti-IL-1β, on patients with ASCVD that had suffered a myocardial infarction (MI)-succeeded in reducing the primary end point (nonfatal MI, stroke, or cardiovascular death) by 15 % (p = 0.02075) (Ridker et al., 2017). ...
In the 20th century, research focused on cholesterol and lipoproteins as the key mechanism in establishing atherosclerotic cardiovascular disease (ASCVD). Given that some studies demonstrated subclinical atherosclerosis in subjects without conventional cardiovascular risk factors, the elevated low-density lipoprotein (LDL) levels alone cannot account for the entire burden of atherosclerosis. Hence, large-scale clinical trials demonstrated the operation of immune and inflammatory pathways in ASCVD. In this regard, the evidence establishes that cells of the immune system, both the innate (neutrophils, macrophages) and adaptive (T cell and other lymphocytes) limbs, contribute to atherosclerosis and atherothrombosis. Besides, basic science studies have identified proatherogenic cytokines such as interleukin (IL)-1, IL-12, and IL-18. In this regard, some studies showed that antiinflammatory therapy targeting the immune system by modulating or blocking interleukins, also known as anti-cytokine therapy, can reduce the risk of major cardiovascular adverse events. The neutrophils play a key role in the innate immune system, representing the acute phase of an inflammatory response. In contrast, lymphocytes represent the adaptive immune system and promote the induction of autoimmune inflammation, especially in the chronic inflammatory response. Through the literature review, we will highlight the inflammatory pathway for the physiopathology of ASCVD, HF, and COVID-19. In this regard, the neutrophil-to-lymphocyte ratio (NLR) integrates the innate immune and adaptive immune systems, making the NLR a biomarker of inflammation. In addition, we provided an update on the evidence showing that high NLR is associated with worse prognosis in heart failure (HF), ASCVD, and COVID-19, as well as their clinical applications showing that the normalization of NLR after anti-cytokine therapy is a potential predictor of therapy responsiveness and is associated with reduction of major adverse cardiovascular events.
... Recent research has identified IL-1β and IL-18 as the most important inflammatory cytokines that promote atherosclerosis development [60]. IL-1β is primarily expressed in myeloid cells, including macrophages and DCs, and in other cell types, such as endothelial cells and fibroblast. ...
Endothelial dysfunction (ED) is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and inflammatory factors, as well as deficiency of nitric oxide (NO) bioavailability. It has been reported that the maintenance of endothelial cell integrity serves a significant role in human health and disease due to the involvement of the endothelium in several processes, such as regulation of vascular tone, regulation of hemostasis and thrombosis, cell adhesion, smooth muscle cell proliferation, and vascular inflammation. Inflammatory modulators/biomarkers, such as IL-1α, IL-1β, IL-6, IL-12, IL-15, IL-18, and tumor necrosis factor α, or alternative anti-inflammatory cytokine IL-10, and adhesion molecules (ICAM-1, VCAM-1), involved in atherosclerosis progression have been shown to predict cardiovascular diseases. Furthermore, several signaling pathways, such as NLRP3 inflammasome, that are associated with the inflammatory response and the disrupted H2S bioavailability are postulated to be new indicators for endothelial cell inflammation and its associated endothelial dysfunction. In this review, we summarize the knowledge of a plethora of reviews, research articles, and clinical trials concerning the key inflammatory modulators and signaling pathways in atherosclerosis due to endothelial dysfunction.
... Feeding the HFHC diet feeding induces the expression of multiple genes, including specific transcription factors (TFs) which activate specific proinflammatory pathways 43 . In the current study, the integration of liver TF binding sites with gene expression and genetic regulation yielded associations between atherosclerosis and specific TFs. ...
Atherogenesis is an insipidus but precipitating process leading to serious consequences of many cardiovascular diseases (CVD). Numerous genetic loci contributing to atherosclerosis have been identified in human genome-wide association studies, but these studies have limitations in the ability to control environmental factors and to decipher cause/effect relationships. To assess the power of hyperlipidemic Diversity Outbred (DO) mice in facilitating quantitative trait loci (QTL) analysis of complex traits, we generated a high-resolution genetic panel of atherosclerosis susceptible (DO-F1) mouse cohort by crossing 200 DO females with C57BL/6J males carrying two human genes: encoding apolipoprotein E3-Leiden and cholesterol ester transfer protein. We examined atherosclerotic traits including plasma lipids and glucose in the 235 female and 226 male progeny before and after 16 weeks of a high-fat/cholesterol diet, and aortic plaque size at 24 weeks. We also assessed the liver transcriptome using RNA-sequencing. Our QTL mapping for atherosclerotic traits identified one previously reported female-specific QTL on Chr10 with a narrower interval of 22.73 to 30.80 Mb, and one novel male-specific QTL at 31.89 to 40.25 Mb on Chr19. Liver transcription levels of several genes within each QTL were highly correlated with the atherogenic traits. A majority of these candidates have already known atherogenic potential in humans and/or mice, but integrative QTL, eQTL, and correlation analyses further pointed Ptprk as a major candidate of the Chr10 QTL, while Pten and Cyp2c67 of the Chr19 QTL in our DO-F1 cohort. Finally, through additional analyses of RNA-seq data we identified genetic regulation of hepatic transcription factors, including Nr1h3, contributes to atherogenesis in this cohort. Thus, an integrative approach using DO-F1 mice effectively validates the influence of genetic factors on atherosclerosis in DO mice and suggests an opportunity to discover therapeutics in the setting of hyperlipidemia.
... Kaitannya terhadap aterosklerosis bahwa AND memiliki efek menghambat sitokin proinflamasi pada aterosklerosis. IL-1β dan TNF-α termasuk sitokin yang memiliki peran penting dalam respon inflamasi dan sejumlah besar penelitian telah dicoba untuk menggambarkan peran sitokin ini dalam aterogenesis [12]. Setelah mengikat IL-1 reseptor (IL-1R), IL-1 menginduksi produksi sitokin dan kemokin serta ekspresi adhesi molekul pada sel endotel (EC), sehingga mengarah keperekrutan sel inflamasi. ...
... Setelah mengikat IL-1 reseptor (IL-1R), IL-1 menginduksi produksi sitokin dan kemokin serta ekspresi adhesi molekul pada sel endotel (EC), sehingga mengarah keperekrutan sel inflamasi. Selain itu, IL-1 berkontribusi untuk perkembangan kerusakan vaskular dengan merangsangproliferasi dan diferensiasi sel serta pelepasan enzim pengurai matriks (8) (12). IL-1β adalah faktor penting diferensiasi sel Th17 yang dapat memperburuk peradangan pada dinding pembuluh darah. ...
The focus is how the role of cytokines in atherosclerosis as a chronic inflammatory disease, as it is known that cytokines regulate complex inflammatory responses in atherosclerotic plaques, especially IL-1β. Sambiloto (Andrographis paniculata) is a plant with various pharmacological activities. Andrographolide (AND) is the main bioactive compound in the diterpene lactone group. This literature study aims to assess the potential of AND on the proinflammatory cytokine IL-1 β as an antiatherosclerosis. This type of research is a qualitative review of various studies using sambiloto plants or andrographolide compounds (AND). Search literature using the Google Scholar database. Keywords used "Andrographis paniculata, andrographolide, IL-1β, Atherosclerosis. The results showed that AND has effects as an anti-inflammatory, antiatherosclerosis as well as cardiovascular-related diseases. There are not many articles on the activity of AND in IL-1β against atherosclerosis, but AND can provide inhibitory activity of the cytokine IL-1β against inflammation. Not many researchers have discussed the pharmacological effects of AND as an antiatherosclerotic on IL-1β therapeutic targets, but from the results of the review AND has a strong potential in inhibiting IL-1 cytokine secretion β.
... Notably, the efficacy of anti-inflammatory therapy in human atherosclerosis has been recently validated 37,38 . Several pro-inflammatory cytokines are atherogenic in humans and mice [39][40][41] . These include MCP-1, implicated in infiltrating immune cells into the vessel wall, an essential component of atherosclerosis progression 42 . ...
Ketogenic diets (KD) are very low-carbohydrate diets that promote nutritional ketosis and are widely used for weight loss, although concerns about potential adverse cardiovascular effects remain. In this study, we used apolipoprotein E deficient ( ApoE -/- ) mice to investigate the vascular impact and plasma metabolic signature of a very high-fat KD compared to a non-ketogenic high-fat diet (HFD). Plasma samples were collected after 4, 8, and 12 weeks on the experimental diets and used to quantify the major ketone body β-hydroxybutyrate (BHB), inflammatory cytokines (interleukin 6, IL-6; monocyte chemoattractant protein 1, MCP-1; and tumor necrosis factor α, TNF-α), and targeted metabolomic profiling by mass spectrometry. Moreover, aortic atherosclerotic lesions were quantified ex vivo by magnetic resonance imaging (MRI) on a 14-tesla system. The results showed that, relative to HFD mice, the KD mice had markedly higher levels of BHB and lower levels of cytokines, confirming the presence of ketosis that alleviated the well-established fat-induced systemic inflammation. Moreover, mice under nutritional ketosis displayed a distinct plasma amino acid profile evidencing a KD-induced alteration in protein metabolism. Significant changes in the plasma metabolome in KD mice included a decrease in lipophilic and increase in hydrophilic metabolites. Despite the higher fat content of the KD versus the HFD, KD mice presented significantly lower levels of several lipid metabolites, including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides. Consistent with the shift in energy metabolism toward fatty acid oxidation caused by the KD, the ratio of acylcarnitines to free carnitine was significantly higher in KD than in HFD mice., the aortic plaque burden was significantly lower in the KD versus the HFD group. In conclusion, nutritional ketosis induced by the KD was associated with specific metabolic changes and an atheroprotective phenotype versus the HFD.
... [32,33] Inflammation impairs normal endothelial function, accelerates the formation of unstable atherosclerotic plaque, and contributes to plaque rupture and thrombosis. [34,35] Fibrous cap thickness is one of the most important determinants of plaque vulnerability. Vulnerable atherosclerotic plaques are heavily infiltrated by macrophage foam cells, which release multiple inflammatory mediators and cytokines, such as plasminogen activators, cathepsins, and matrix metalloproteinases; this finally results in matrix degradation, fibrous cap thinning, and plaque rupture, leading to a severe cardiovascular event. ...
... Thus, IL-10 modulation has been investigated as a possible therapeutic strategy in experimental atherosclerosis [12,[15][16][17]. This cytokine is known to be produced by several leukocytes, most notably macrophages [34]. ...
Atherosclerosis is initiated by subendothelial retention of lipoproteins and cholesterol, which triggers a non-resolving inflammatory process that over time leads to plaque progression in the artery wall. Myeloid cells and in particular macrophages are the primary drivers of the inflammatory response and plaque formation. Several immune cells including macrophages, T cells and B cells secrete the anti-inflammatory cytokine IL-10, known to be essential for the atherosclerosis protection. The cellular source of IL-10 in natural atherosclerosis progression is unknown. This study aimed to determine the main IL10-producing cell type in atherosclerosis. To do so, we crossed VertX mice, in which IRES-green fluorescent protein (eGFP) was placed downstream of exon 5 of the Il10 gene, with atherosclerosis-prone Apoe−/− mice. We found that myeloid cells express high levels of IL-10 in VertX Apoe−/− mice in both chow and western-diet fed mice. By single cell RNA sequencing and flow cytometry analysis, we identified resident and inflammatory macrophages in atherosclerotic plaques as the main IL-10 producers. To address whether IL-10 secreted by myeloid cells is essential for the protection, we utilized LyzMCre+Il10fl/fl mice crossed into the Apoe−/− background and confirmed that macrophages were unable to secrete IL-10. Chow and western diet-fed LyzMCre+Il10fl/fl Apoe−/− mice developed significantly larger atherosclerotic plaques as measured by en face morphometry than LyzMCre−Il10 fl/flApoe−/−. Flow cytometry and cytokine measurements suggest that the depletion of IL-10 in myeloid cells increases Th17 cells with elevated CCL2, and TNFα in blood plasma. We conclude that macrophage-derived IL-10 is critical for limiting atherosclerosis in mice.
... TNF induces the production of cytokines such as IL-6 and is involved in the inflammatory process of several diseases, including IHD and depression. [59][60][61][62] In addition, anti-inflammatory cytokines, such as IL-4 and IL-10, are involved in the development of IHD and depression and are important targets for improving these disease conditions. 63-66 PPARG plays a central role in controlling lipid metabolism and is involved in pathological processes such as obesity, diabetes, and atherosclerosis. ...
Objective: This study aimed to explore the potential targets and mechanism of action of Danshen in treating concurrent ischemic heart disease (IHD) and depression using network pharmacology, molecular docking, and molecular dynamics simulation (MDS). Methods: The Traditional Chinese Medicine Systems Pharmacology (TCMSP) database was used to obtain active ingredients and targets of Danshen. Candidate targets for IHD and depression were obtained from the Genecards and DisGeNet databases. The protein–protein interaction (PPI) network was constructed using the STRING database and the Cytoscape 3.8.2 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the Metascape database and the GlueGO package of the Cytoscape 3.8.2 software. Molecular docking was performed using Autodock 1.5.6 and Vina, and the MDS was completed using GROMACS 5.1.2. Results: We obtained 65 active ingredients of Danshen with 131 candidate targets and 39 intersection targets of the active ingredients and diseases. Luteolin, tanshinone IIA, and salviolone were the core active ingredients, and AKT1, TNF, IL-6, MMP9, CASP3, IL-10, PTGS2, STAT3, PPARG, IL-4, EGFR, MAPK14, NOS3, and EDN1 were the core targets. The GO and KEGG pathway enrichment analyses revealed that the intersection targets were mainly enriched in positive regulation of protein phosphorylation, blood circulation, IL-17 signaling pathway, VEGF signaling pathway, and JAK/STAT signaling pathway. The molecular docking revealed that the core active ingredients had a good affinity for the core targets. The results of MDS revealed that the protein-ligand complexes were stable. Conclusions: This study used network pharmacology to analyze the potential mechanism of action of Danshen in the treatment of concurrent IHD and depression. Additionally, the study provided a theoretical basis for further studying the pharmacological mechanisms and targets of Danshen.
... Among all IL-1 family cytokines, IL-1a, IL-1b, IL-18 and IL-1Ra are the most extensively studied members (48). In recent years, interleukin-1b (IL-1b) and interleukin-18 (IL-18) have been identified as the two most important inflammatory cytokines that promote the development of atherosclerosis (76). ...
Atherosclerosis is a lipid-driven chronic inflammatory disease that is widespread in the walls of large and medium-sized arteries. Its pathogenesis is not fully understood. The currently known pathogenesis includes activation of pro-inflammatory signaling pathways in the body, increased oxidative stress, and increased expression of cytokines/chemokines. In the innate immune response, inflammatory vesicles are an important component with the ability to promote the expression and maturation of inflammatory factors, release large amounts of inflammatory cytokines, trigger a cascade of inflammatory responses, and clear pathogens and damaged cells. Studies in the last few years have demonstrated that NLRP3 inflammatory vesicles play a crucial role in the development of atherosclerosis as well as its complications. Several studies have shown that NLRP3 binding to ligands promotes inflammasome formation, activates caspase-1, and ultimately promotes its maturation and the maturation and production of IL-1β and IL-18. IL-1β and IL-18 are considered to be the two most prominent inflammatory cytokines in the inflammasome that promote the development of atherosclerosis. SGLT2 inhibitors are novel hypoglycemic agents that also have significant antiatherosclerotic effects. However, their exact mechanism is not yet clear. This article is a review of the literature on the effects and mechanisms of SGLT2 inhibitors on the NLRP3 inflammasome, focusing on their role in antiatherosclerosis.
